Frequency and clinical relevance of coding and noncoding <i>NOTCH1</i> mutations in early stage Binet A chronic lymphocytic leukemia patients

Lionetti, Marta; Barbieri, Marzia; Favasuli, Vanessa; Taìana, Elisa; Fabris, Sonia; Favoino, Chiara; Ciceri, Gabriella; Matis, Serena; Colombo, Monica; Massara, Rosanna; Reda, Gianluigi; Gentile, Massimo; Spina, Valeria; Rossi, Davide; Baldini, Luca; Gaïdano, Gianluca; Fais, Franco; Ferrarini, Manlio; Morabito, Fortunato; Cutrona, Giovanna; Neri, Antonino

doi:10.1002/hon.2722

Cited by 5 publications

(8 citation statements)

References 8 publications

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Section: Discussionsupporting

confidence: 92%

“…Similarly, the same prognostic indicators were demonstrated by our group to be independently associated with TTFT together with LDT. Unlike CLL1-PM, NOTCH1 remained significant in our analysis, confirming previous results (3,5,18). Remarkably, the higher prognostic value, provided by risk prediction score including LDT, found in the training cohort was fully confirmed in the two validation cohorts.…”

Section: Discussionsupporting

confidence: 89%

“…An independent cohort of newly diagnosed and prospectively followed CLL patients recruited since 2001 at the Division of Hematology, Department of Translational Medicine, UPO, Novara, Italy, was utilized as a first validation cohort. The present analysis was restricted to 276, with LDT available, out of 283 cases included in a previous paper ( 5 ). All the prognostic factors required in this study ( IGHV mutational status, Rai stage, β2M, 17(p) and 11(q) deletions, NOTCH1 coding gene mutation, and LDT were available for 257 cases.…”

Section: Methodsmentioning

confidence: 99%

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Lymphocyte Doubling Time As A Key Prognostic Factor To Predict Time To First Treatment In Early-Stage Chronic Lymphocytic Leukemia

et al. 2021

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The prognostic role of lymphocyte doubling time (LDT) in chronic lymphocytic leukemia (CLL) was recognized more than three decades ago when the neoplastic clone’s biology was almost unknown. LDT was defined as the time needed for the peripheral blood lymphocyte count to double the of the initial observed value. Herein, the LDT prognostic value for time to first treatment (TTFT) was explored in our prospective O-CLL cohort and validated in in two additional CLL cohorts. Specifically, newly diagnosed Binet stage A CLL patients from 40 Italian Institutions, representative of the whole country, were prospectively enrolled into the O-CLL1-GISL protocol (clinicaltrial.gov identifier: NCT00917540). Two independent cohorts of newly diagnosed CLL patients recruited respectively at the Division of Hematology in Novara, Italy, and at the Hospital Clinic in Barcelona, Spain, were utilized as validation cohorts. In the training cohort, TTFT of patients with LDT >12 months was significantly longer related to those with a shorter LDT. At Cox multivariate regression model, LDT ≤ 12 months maintained a significant independent relationship with shorter TTFT along with IGHV unmutated (IGHVunmut) status, 11q and 17p deletions, elevated β2M, Rai stage I-II, and NOTCH1 mutations. Based on these statistics, two regression models were constructed including the same prognostic factors with or without the LDT. The model with the LTD provided a significantly better data fitting (χ2 = 8.25, P=0.0041). The risk prediction developed including LDT had better prognostic accuracy than those without LDT. Moreover, the Harrell’C index for the scores including LDT were higher than those without LDT, although the accepted 0.70 threshold exceeded in both cases. These findings were also confirmed when the same analysis was carried out according to TTFT’s explained variation. When data were further analyzed based on the combination between LDT and IGHV mutational status in the training and validation cohorts, IGHVunmut and LDT>12months group showed a predominant prognostic role over IGHVmut LTD ≤ 12 months (P=0.006) in the O-CLL validation cohort. However, this predominance was of borden-line significance (P=0.06) in the Barcelona group, while the significant prognostic impact was definitely lost in the Novara group. Overall, in this study, we demonstrated that LDT could be re-utilized together with the more sophisticated prognostic factors to manage the follow-up plans for Binet stage A CLL patients.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 89%

Section: Methodsmentioning

confidence: 99%

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Lymphocyte Doubling Time As A Key Prognostic Factor To Predict Time To First Treatment In Early-Stage Chronic Lymphocytic Leukemia

et al. 2021

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“…CD38 and ZAP-70 expression, β2-microglobulin (β2M) serum levels, Rai stage, IGHV mutational status, del(11q), NOTCH1 and SF3B1 mutations, MBL classification were confirmed to have a significant prognostic power on univariate analysis 27 (Supplementary Table 5 ). A Cox multivariate analysis was then performed by introducing into the model markers indicative of TP53 alterations together with the variables with a significant prognostic power for TTFT determined in the univariate analysis.…”

Section: Resultsmentioning

confidence: 92%

“…Statistical analyses were performed as previously described 25 , 27 . Briefly, SPSS for Windows, v13.0, 2004 software (SPSS, UK) was used for all the analyses.…”

Section: Methodsmentioning

confidence: 99%

Time to first treatment and P53 dysfunction in chronic lymphocytic leukaemia: results of the O-CLL1 study in early stage patients

Monti

Lionetti

Luca

et al. 2020

Sci Rep

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Chronic lymphocytic leukaemia (CLL) is characterised by a heterogeneous clinical course. Such heterogeneity is associated with a number of markers, including TP53 gene inactivation. While TP53 gene alterations determine resistance to chemotherapy, it is not clear whether they can influence early disease progression. To clarify this issue, TP53 mutations and deletions of the corresponding locus [del(17p)] were evaluated in 469 cases from the O-CLL1 observational study that recruited a cohort of clinically and molecularly characterised Binet stage A patients. Twenty-four cases harboured somatic TP53 mutations [accompanied by del(17p) in 9 cases], 2 patients had del(17p) only, and 5 patients had TP53 germ-line variants. While del(17p) with or without TP53 mutations was capable of significantly predicting the time to first treatment, a reliable measure of disease progression, TP53 mutations were not. This was true for cases with high or low variant allele frequency. The lack of predictive ability was independent of the functional features of the mutant P53 protein in terms of transactivation and dominant negative potential. TP53 mutations alone were more frequent in patients with mutated IGHV genes, whereas del(17p) was associated with the presence of adverse prognostic factors, including CD38 positivity, unmutated-IGHV gene status, and NOTCH1 mutations.

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LINC00152 expression in normal and Chronic Lymphocytic Leukemia B cells

Matis

Rossi

Brondolo

et al. 2021

Hematological Oncology

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Long non‐coding RNAs are emerging as essential regulators of gene expression, but their role in normal and neoplastic B cells is still largely uncharacterized. Here, we report on the expression pattern of the LINC00152 in normal B cells and Chronic Lymphocytic Leukemia B cell clones. Higher LINC00152 levels were consistently observed in memory B cell populations when compared to naïve B cells in the normal tissues analyzed [peripheral blood (PB), tonsils, and spleen]. In addition, independent stimulation via Immunoglobulins (IG), CD40, or Toll‐like Receptor 9 (TLR9) upregulated LINC00152 in PB B cells. The expression of LINC00152 in a cohort of 107 early stage Binet A CLL patients was highly variable and did not correlate with known prognostic markers or clinical evolution. TLR9 stimulation, but not CD40 or IG challenge, was able to upregulate LINC00152 expression in CLL cells. In addition, LINC00152 silencing in CLL cell lines expressing LINC00152 failed to induce significant cell survival or apoptosis changes. These data suggest that, in normal B cells, the expression of LINC00152 is regulated by immunomodulatory signals, which are only partially effective in CLL cells. However, LINC00152 does not appear to contribute to CLL cell expansion and/or survival in a cohort of newly diagnosed CLL patients.

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Frequency and clinical relevance of coding and noncoding NOTCH1 mutations in early stage Binet A chronic lymphocytic leukemia patients

Cited by 5 publications

References 8 publications

Lymphocyte Doubling Time As A Key Prognostic Factor To Predict Time To First Treatment In Early-Stage Chronic Lymphocytic Leukemia

Lymphocyte Doubling Time As A Key Prognostic Factor To Predict Time To First Treatment In Early-Stage Chronic Lymphocytic Leukemia

Time to first treatment and P53 dysfunction in chronic lymphocytic leukaemia: results of the O-CLL1 study in early stage patients

LINC00152 expression in normal and Chronic Lymphocytic Leukemia B cells

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